Field of the Invention
The present invention lies firmly within the fields of drug, bio-effective and body treating compositions, more specifically a method for transporting chimeric hybrid molecules across the blood brain barrier (BBB). The present invention will be especially useful for transporting analgesic molecules possessing complex chemical structures consisting of one or more functional domains across the BBB to achieve acute and chronic pain relief or pharmaceutical amelioration of pain-related pathophysiological conditions.
Description of the Prior Art
The present invention relates to transporting novel hybrid alkaloid/peptide chimeric molecules across the BBB through the use of an alkaloid moiety.
Transporting analgesic compounds across the BBB is useful for achieving efficacious analgesia. The relief of suffering due to pain is an important objective of clinical practice and for restoring quality to life and the ability to function normally to pain sufferers.
Pain represents an integrated, complex, perception of noxious stimuli originating from somatic elements such as arms and legs and/or from visceral organs such as heart and liver.
Mechanistically, acute pain signaling involves noxious stimulation of free nerve endings innervating somatic elements and/or visceral organs leading to the activation of different types of slowly-conducting afferent fibers and of the A delta and C classes, terminating in the dorsal sensory spinal cord. A significantly more complex etiology underlies the initiation and persistence of chronic pain syndromes. This involves initial damage to peripheral nerves innervating somatic and visceral fields, persistent immunological challenge by cytokines and inflammatory mediators, reorganization of spinal cord and brainstem relay systems, and higher cortical adaptation.
From an established pharmacological perspective, opioids remain the key agents of choice for treatment of a wide variety of acute and chronic pain states. The prototype opioid analgesic or painkiller is morphine. Morphine and morphine-related opioids produce their painkilling effects by profound pharmacological inhibition of neurons of the peripheral/sensory nervous system (PNS) and the central nervous system (CNS). The biochemical and cellular effects of morphine, including potent analgesia, are transduced through a membrane-associated G-protein designated the mu (μ) opioid receptor (MOR), found in high concentrations within the PNS and CNS. In a prior invention (U.S. Pat. No. 5,891,842), I established a therapeutic procedure or treatment regimen for inducing or eliciting a markedly enhanced opioid-dependent analgesic response within a living subject. That treatment methodology employs the concurrent administration of two recognized, self-contradicting and physiologically antagonistic compounds, the opioid analgesic morphine sulfate and the tachykinin peptide substance P (SP), at individual concentrations that had been empirically shown to have either marginal or completely ineffectual pharmacological properties in vivo. Because noxiously challenged or damaged sensory nerves release a variety of excitatory chemical mediators, including SP, the tachykinin SP had been previously designated as a nociceptive or pain-producing peptide transmitter at the spinal level. Nevertheless, my research demonstrates that at prescribed low nanogram concentrations SP appears to be a potent regulator of opioid analgesia in vivo.
Despite this apparent contradiction and the previously demonstrated physiological antagonism between these compounds in their traditional formats and conventionally used concentrations, my novel treatment process demonstrated a synergistic relationship over a period of time, and that an effective and efficacious opioid-induced analgesia results within the living subject from the process.
Unfortunately, because my prior invention requires the concurrent administration of two different self-contradicting and physiologically antagonistic compounds, SP and morphine, it presents difficulties in successfully establishing and testing the appropriate concurrent dosages for efficacious and safe administration in humans, as reflected by FDA and NIH clinical testing guidelines. This includes differences in the ability of morphine and of SP to cross the BBB.
While morphine is the prototype opioid analgesic or painkiller, its complex alkaloid characteristics differ greatly from those of peptides, and SP is a peptide. In subsequent research, therefore, collaborators and I combined the active pharmacological domains of SP and the peptide endomorphin-2 into one chemical entity: a novel seven amino acid peptide chimera, designated ESP7. Repeated administration of the chimeric molecule into the rat spinal cord milieu produced analgesia mediated by the MOR without a loss of potency over a 5-day time course. Essentially, ESP7 represented a non-tolerance forming compound with future potential as a specialized spinal analgesic for control of acute and/or chronic pain. (Foran, et al., A Substance P-opioid chimeric peptide as a unique non-tolerance-forming analgesic, 97 Proceedings of the National Academy of Sciences 13 (2000))
Although ESP7 provided the advantage of a single analgesic molecule, it has several unifortunate disadvantages. Operationally, the peptide chemical nature of ESP7 restricts its effective dosage and time-effect relationship within the CNS due to significant metabolism in the blood stream. This is supported by collected pharmacological data indicating significant difficulties encountered by peptide drug candidates for crossing the mammalian BBB (Eggleton R D, Abbruscato T J, Thomas S A, Davis T P Transport of opioid peptides into the central nervous system. J Pharm Sci 1998; 87(11):1433–9).
Morphine is a relatively complex organic molecule, termed an alkaloid due to its positively charged nitrogen group, unlike the endogenous peptide endomorphin-2 which provided the analgesic moiety in ESP7. Morphine is a highly efficacious MOR-selective opioid analgesic and will cross the human BBB, as will its active metabolite morphine 6-glucuronide. (Stain-Texier F, Boschi G, Sandouk P, Scherrmann J M, Elevated concentration of morphine 6-beta-D-glucuronide in brain extracellular fluid despite low blood-brain barrier permeability. Br J Pharmacol 1999; 128(4):917–24) SP, however, is a peptide. Chimeric hybrid molecules possessing an alkaloid moiety and a peptide moiety are unknown to the literature of analgesia and to clinical practice. Chimeric hybrid molecules possessing an alkaloid moiety to activate the human MOR and a peptide moiety to concurrently activate the human SP receptor (SPR) are unknown to the literature of analgesia and to clinical practice. Chimeric hybrid molecules comprised of one moiety with a chemically modified morphine molecule to activate the human MOR and another moiety with a SP fragment to activate the human SPR are unknown to the literature of analgesia and to clinical practice. The method of inhibiting the development of opioid tolerance using such chimeric hybrid molecules is unknown to the literature of analgesia and to clinical practice.
Another major challenge is to design a molecule that will cross the BBB and produce analgesia in a living subject, while inhibiting tolerance development and dependence formation. Peptides do not readily cross the BBB. To achieve the analgesic effects I envisioned, a chimeric compound that activates both an MOR and SPR must cross the BBB. Such a molecule should be structured in such a way as to activate simultaneously the MOR and SPR domains in the PNS and/or CNS. With respect to both morphine and SP, a variety of alkaloid morphine and SP peptide fragments can be synthesized, having potentially different pharmacological effects if bound to another moiety. No obvious method is known for the SP moiety to be cross-linked to a morphine alkaloid moiety in a fashion that the resulting molecule will allow simultaneous activation of both the MOR and SPR receptors. Chimeric hybrid molecules with a moiety comprised of a chemically modified morphine molecule to provide the method to transport active SP fragments across the mammalian blood brain barrier are unknown to the literature of analgesia and to clinical practice.
The novelty of the present invention is not predictable according to the teachings of Syvanen and coworkers Syvanen, S., Xie, R., Sahin, S. & Hammarlund-Udenaes, M. (2006) Pharmacokinetic consequences of active drug efflux at the blood-brain barrier. Pharm. Res. 23, 705–717) who studied influx and efflux process of morphine and morphine-glucuronides in relation to their BBB permeability properties and brain concentrations. Syvanen and coworkers teach that efficacious BBB permeation is determined by a combination of influx hindrance (a gatekeeper function in the luminal membrane that is functionally linked to P-glycoproptein activation) and efflux enhancement by transports that pick up molecules on one side of the luminal or abluminal membrane and release them on the other side. The facilitative method of BBB transport of morphine and morphine congeners by covalently bonded heterologous SPR activating domains as found in the structure of chimeric hybrid conjugate molecules is not predictable by the general principle of BBB permeation by morphine and morphine congeners codified by Syvanen and coworkers. Conversely, the facilitative method of BBB transport of SP fragments or non-peptide SPR activating domains by covalently bonded heterologous morphine, morphine congeners, and opioid peptide MOR activating domains as found in the structure of chimeric hybrid conjugate molecules is not predictable by the teachings of Syvanen and coworkers.
Presently there also are no analgesic opioid chimeras that have crossed the BBB to achieve effective analgesia for mammalian acute or chronic pain without significant tolerance development and dependence formation.
Objects and Advantages
I have invented novel and useful methods employing heretofore unknown morphine-SP hybrid chimeras, as I have described below. Several objects and advantages of my present invention are:                a. a method for transporting, across the BBB, a molecule that can be dosed to produce effective analgesia in a living subject, i.e., a mammal (an animal class which includes humans),while inhibiting tolerance development;        b. a method for transporting, across the BBB, a molecule that can be dosed to produce effective analgesia in a living subject while inhibiting dependence formation;        c. a method for transporting, across the BBB, a molecule that can be dosed to produce effective opioid analgesia and that can be administered through a variety of methods of clinical administration, including oral, systemic and epidural administration;        d. A method for transporting, across the BBB, a molecule that can be dosed to produce effective opioid analgesia without significant restriction on its effective dosage and time-effect relationship within the CNS due to metabolism in the blood stream;        e. a method for transporting, across the BBB, a molecule that can be dosed to yield effective opioid analgesia with a reduction in the likelihood of undesirable side effects;        f. a method for transporting, across the BBB, a molecule that can be dosed to produce effective opioid analgesia with a reduction in the likely severity of undesirable side effects that become manifested by the patient;        g. a method for transporting, across the BBB, an opioid analgesic that can be dosed for administration to children without undue tolerance development;        h. a method for transporting, across the BBB, an opioid analgesic that can be dosed for administration to children without undue dependence formation; and        i. a method for transporting, across the BBB, an opioid analgesic suitable for PCA in the treatment of chronic and/or acute pain.        
Additional objects and advantages of my present invention are:                a. to provide a method for transporting a chimeric molecule across the BBB so as to treat pain with opioid analgesia and little or no opioid tolerance development;        b. to provide a method for transporting a chimeric molecule across the BBB so as to treat pain with opioid analgesia and little or no opioid dependence formation;        c. to provide a method for transporting a chimeric molecule across the BBB so as to treat pain with opioid analgesia with reduced likelihood of undesirable side effects;        d. to provide a method of transporting a chimeric molecule across the BBB so as to provide opioid analgesia for PCA for acute and/or chronic pain; and        e. to provide a method of transporting a chimeric molecule across the BBB so as to treat drug abuse by administering as a substitute for the abused drug an analgesic that elicits little or no tolerance development or dependency formation and thereafter adjusting the dosage as tolerance and/or dependence is modulated.        
Still further objects and advantages will become apparent from a consideration of the following description of my invention.